It is found that most orally administered polypeptide and protein (such as insulin) drugs cannot be well absorbed for the reasons that the polypeptides and proteins contained therein are readily decomposed in the stomach, and/or cannot penetrate the intestinal mucosa cells due to their large molecular size and their hydrophilic property. Even if the polypeptides and proteins can be absorbed, they can hardly avoid the first-pass effect in the liver. Therefore, the bioavailability of all polypeptide and protein drugs is too low (<2%) to achieve a good therapeutic effect (A. E. Pontiroli et al., Clin. Pharmacokinet., 17(5): 299-307, 1989). In view of the above, polypeptide and protein drugs are generally administered by injection. However, this administration manner brings the patients, who need a long-term treatment, a lot of agony so as to seriously affect their compliance. Thus, non-oral administration routes, such as nasal, buccal, anal, ocular, and pulmonary administrations, have been developed.
Since pulmonary mucosa has a large surface area to provide good absorption and penetrability, polypeptide and protein drugs can be rapidly absorbed through pulmonary mucosa. This method can not only avoid the destruction or the metabolism of the polypeptide and protein drugs in the stomach and intestine, as well as the first-pass effect in the liver, but also increase the bioavailability of the drugs and improve the convenience for and compliance of the patients (Z. Shao et al., Pharm. Research, Vo. 11, No. 2, p. 243-250, 1994). Furthermore, the drugs can directly enter the major targeted organs so as to reduce the side effects generated by injection. Therefore, the pulmonary delivery has the most potential for polypeptide and protein drugs.
However, as stated by Patton et al. (Clin. Pharmacokinet, 2004: 43(12) 781-801), absorption enhancers in the pulmonary absorbed agents can improve the absorption of the drugs, but may also cause toxicity in the lung. For example, absorption enhancers may stimulate the increase of the eosinophil in the lung and result in an allergic reaction, or cause the increase of the neutrophil to induce acute inflammation in the lung. Even more, absorption enhancers may increase the production of LDH enzyme and/or the infiltration of proteins into the blood to cause toxic reactions or injuries in the pulmonary tissues and cells.
The present invention provides an aqueous inhalation pharmaceutical composition of a polypeptide or protein, which has improved bioavailability and reduced lung toxicity.